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Drug Reference

tramadol

opioid analgesic· Brands: Ultram, Zydol, Tramal, ConzipIMIVPOPR

Mechanism of action
Tramadol is a centrally acting analgesic with two complementary actions. It is a weak agonist at mu-opioid receptors and inhibits neuronal reuptake of noradrenaline and serotonin, which enhances descending inhibitory pain pathways. The parent drug has low mu-opioid potency; hepatic CYP2D6 converts it to O-desmethyltramadol (M1), which has greater mu-opioid receptor affinity and contributes much of the analgesic effect. Analgesia therefore depends on both opioid and monoaminergic mechanisms, and genetic or drug-induced variation in CYP2D6 activity alters response.
Pharmacokinetics
After oral doses tramadol is well absorbed, with bioavailability around 70 to 75 per cent because of first-pass metabolism. It is metabolised in the liver by CYP2D6 and CYP3A4 to several metabolites, including the active M1. Onset of analgesia is typically within an hour after immediate-release oral doses, and the elimination half-life of tramadol is about 6 hours, with M1 somewhat longer. Tramadol and its metabolites are excreted mainly renally, so dose reduction and longer intervals are needed in renal impairment and in older adults. CYP2D6 poor metabolisers may obtain less analgesia, while ultrarapid metabolisers may be at greater risk of opioid toxicity.
Indications & dosing

Moderate to severe acute pain

Immediate-release. Start at 50 mg in elderly or hepatic impairment; maximum 300 mg/day in patients over 75 years. Adjust in renal impairment.

  • adult · PO: 50–100 mg every 4-6 hours · Immediate-release. Start at 50 mg in elderly or hepatic impairment; maximum 300 mg/day in patients over 75 years. Adjust in renal impairment.

Chronic persistent pain

Extended-release formulation; titrate slowly. Not for acute breakthrough pain. Avoid in severe renal or hepatic impairment.

  • adult · PO: 100–300 mg once daily · Extended-release formulation; titrate slowly. Not for acute breakthrough pain. Avoid in severe renal or hepatic impairment.

Postoperative pain

IV or IM administration; inject slowly. Reduce dose in renal impairment. Monitor for respiratory depression and seizures.

  • adult · IV: 50–100 mg every 4-6 hours · IV or IM administration; inject slowly. Reduce dose in renal impairment. Monitor for respiratory depression and seizures.

Neuropathic painoff-label

Off-label; evidence is limited. Consider as second-line after tricyclic antidepressants or gabapentinoids. Not first-line therapy.

  • adult · PO: 50–100 mg every 4-6 hours · Off-label; evidence is limited. Consider as second-line after tricyclic antidepressants or gabapentinoids. Not first-line therapy.

Pain in children aged 12 years and older

Not recommended under 12 years. Contraindicated after tonsillectomy or adenoidectomy in children under 18. Check local formulary for age restrictions.

  • pediatric · PO: 50–100 mg every 4-6 hours · Not recommended under 12 years. Contraindicated after tonsillectomy or adenoidectomy in children under 18. Check local formulary for age restrictions.

Moderate to severe pain in the elderly

Start at 50 mg and titrate slowly. Maximum 300 mg/day due to reduced clearance. Increased risk of falls, confusion and respiratory depression.

  • elderly · PO: 50–100 mg every 4-6 hours · Start at 50 mg and titrate slowly. Maximum 300 mg/day due to reduced clearance. Increased risk of falls, confusion and respiratory depression.
Contraindications & precautions
  • Known hypersensitivity to tramadol or to any excipient in the formulation · Cross-sensitivity with other opioids is uncommon but anaphylaxis and angioedema are reported.
  • Current or recent (within 14 days) use of a monoamine oxidase inhibitor · Risk of serotonin syndrome, seizures and cardiovascular instability. A 14-day washout is required after stopping the MAOI before starting tramadol.
  • Acute or severe respiratory depression, or significant respiratory insufficiency · Opioid component depresses respiratory drive. Avoid in severe COPD, cor pulmonale, acute severe asthma and in any patient needing ventilatory support.
  • Uncontrolled epilepsy or a seizure disorder not stabilised on treatment · Tramadol lowers the seizure threshold. Use is contraindicated in uncontrolled epilepsy and requires specialist assessment if seizures are controlled.
  • Acute intoxication with alcohol, hypnotics, opioids or other centrally acting drugs · Additive CNS and respiratory depression; risk of coma and death.
  • Children under 12 years, and children under 18 after tonsillectomy or adenoidectomy · Regulatory restriction in many countries, based on reports of fatal respiratory depression in children, including ultra-rapid CYP2D6 metabolisers.
  • Severe renal impairment (creatinine clearance below 30 mL/min) · Prolonged-release forms are contraindicated; immediate-release use requires increased dosing intervals and specialist advice.
  • Severe hepatic impairment · Reduced clearance causes accumulation. Prolonged-release tramadol is contraindicated in severe impairment; avoid or use minimum effective dose with close monitoring.
  • Assess seizure risk before prescribing: tramadol lowers the seizure threshold. Avoid in head injury, CNS infection, metabolic disorders and in patients taking other drugs that lower seizure threshold, such as tricyclics, SSRIs or antipsychotics.
  • Do not combine with other serotonergic drugs (SSRIs, SNRIs, MAOIs, triptans, linezolid) without close monitoring; teach patients the features of serotonin syndrome (agitation, tremor, clonus, hyperthermia, tachycardia).
  • Analgesic effect and toxicity vary with CYP2D6 and CYP3A4 activity: poor metabolisers may get little analgesia, ultra-rapid metabolisers more opioid toxicity, and CYP3A4 inhibitors such as macrolides or azoles raise toxicity risk.
  • Reduce the dose and lengthen the interval in older adults, in renal impairment (creatinine clearance 30 to 79 mL/min) and in hepatic impairment. Review sedation, confusion and falls at each dose step.
  • Warn about additive CNS and respiratory depression with alcohol, benzodiazepines, gabapentinoids and other opioids, and advise against driving or operating machinery until the effect is known.
  • Tramadol is a controlled drug in many countries. Review the need for continued therapy regularly, use the lowest effective dose for the shortest time, and taper rather than stop abruptly to avoid withdrawal.
Adverse effects
  • Nausea
  • Dizziness
  • Vomiting
  • Constipation
  • Somnolence and fatigue
  • Dry mouth and sweating
  • Seizuresserious
  • Serotonin syndrome with serotonergic drugsserious
  • Clinically significant respiratory depressionserious
  • Dependence, misuse and withdrawal syndromeserious
Interactions
  • linezolidmajorAvoid co-prescription. If co-administration is considered essential, use the lowest possible doses and monitor frequently for early signs of serotonin syndrome. Consider alternative analgesic agents with no serotonergic activity. If serotonin syndrome is suspected, stop both drugs immediately and provide supportive care.
  • sertralinemajorAvoid combination where possible. If necessary, use the lowest effective doses, prescribe with extreme caution, and monitor the patient closely for signs of serotonin syndrome (e.g., mental status changes, fever, sweating, tremor, hyperreflexia, clonus). Consider a non-serotonergic analgesic such as an NSAID or a pure opioid (e.g., morphine) as an alternative. Advise the patient to seek urgent medical attention if symptoms occur.
  • escitaloprammajorAvoid concurrent use when possible. If the combination is considered necessary, use the lowest effective doses, and monitor patients closely for signs of serotonin syndrome, especially during dose escalation. Educate patients to seek immediate medical attention if they experience symptoms. Consider alternative analgesics with lower serotonergic activity.
  • citaloprammajorAvoid the combination where possible. If co-administration is necessary, use the lowest effective doses of both drugs, and prescribe with caution in patients with pre-existing seizure disorders or cardiac disease. Monitor the patient closely for signs of serotonin syndrome (especially during the first few days) and for seizures. Consider alternative analgesics such as paracetamol, NSAIDs, or non-serotonergic opioids (e.g., oxycodone, morphine) if appropriate. If citalopram dose exceeds 40 mg/day, reassess the need for tramadol. Advise patients to seek immediate medical attention if they develop symptoms such as confusion, muscle twitching, or increased sweating. An ECG may be warranted if there are other risk factors for QT prolongation.
  • fluoxetinemajorAvoid the concurrent use of fluoxetine and tramadol. Choose alternative analgesic or antidepressant drugs. If co-prescription is considered essential, use the lowest possible doses, closely monitor for signs of serotonin syndrome, and inform the patient to seek urgent help. Since fluoxetine inhibits CYP2D6 for at least 2 weeks after stopping, consider this when starting tramadol. Monitor for analgesic response, and do not increase the tramadol dose without specialist advice.
Renal & hepatic adjustment
  • eGFR 30+: No routine dose reduction for eGFR 30 mL/min/1.73 m² or above. Use the lowest effective dose and review regularly, as elderly patients and those with mild renal impairment may still accumulate tramadol.
  • eGFR 15–29.9: Reduce the total daily dose and extend the immediate-release dosing interval to 12 hours; a common teaching maximum is 200 mg/24 hours. Avoid modified-release preparations. Monitor sedation and respiratory rate closely.
  • eGFR 0–14.9: Avoid tramadol in severe renal impairment because of accumulation of tramadol and its active metabolite. If no alternative is suitable, seek specialist advice and use a reduced dose with extended intervals and close monitoring. (avoid)
  • Hepatic impairment (mild): No routine dose adjustment. Use the lowest effective dose and monitor for sedation, respiratory depression and confusion.
  • Hepatic impairment (moderate): Reduce the total daily dose and extend the dosing interval; avoid modified-release preparations. A common teaching maximum is 200 mg/24 hours with regular review.
  • Hepatic impairment (severe): Avoid tramadol in severe hepatic impairment because of reduced clearance and the risk of accumulation and encephalopathy. Use an alternative analgesic and seek specialist advice. (avoid)
Monitoring, pregnancy & toxicity
  • Pain control and function · Before starting and at each dose review.
  • Sedation and conscious level · Before starting, after initiation, after dose increases, and periodically during treatment.
  • Respiratory rate and oxygen saturation · First 24 to 72 hours, after dose increases, in older patients, in renal or hepatic impairment, and with CNS depressants.
  • Seizure risk and seizure threshold · At baseline and when adding or stopping drugs that lower seizure threshold, such as SSRIs, tricyclics, antipsychotics or other opioids.
  • Serotonin syndrome features · When tramadol is combined with SSRIs, SNRIs, MAOIs or other serotonergic drugs.
  • Adverse effects and dependence · At each review: nausea, vomiting, constipation, hypotension, urinary retention, mood change, misuse and withdrawal symptoms.
  • Pregnancy: Use only if the benefit outweighs the risk and safer alternatives are unsuitable. Avoid prolonged use, especially in the third trimester, because it can cause neonatal opioid withdrawal syndrome. Use during labour may cause neonatal respiratory depression; arrange neonatal monitoring if used near delivery. Tramadol is not a first-line opioid in pregnancy; involve obstetric and specialist pain services.
  • Toxicity: Opioid toxidrome: CNS depression, sedation, miosis, respiratory depression, bradycardia, hypotension and coma. Naloxone reverses respiratory depression but may not reverse seizures or serotonin toxicity; because of tramadol's long half-life, observe for recurrence and repeat naloxone as needed. · Support airway, breathing and circulation. Give oxygen and ventilate if needed. Titrate naloxone to respiratory rate and conscious level. Monitor for at least 6 to 8 hours, or longer if modified-release preparation, renal impairment or hepatic impairment. Activated charcoal within 1 to 2 hours if airway is protected and no contraindication.
  • Toxicity: Seizures: generalised tonic-clonic seizures may occur after overdose and occasionally at therapeutic doses, especially with a history of epilepsy, head injury or concurrent proconvulsant drugs. · Protect the airway and give a benzodiazepine such as diazepam or lorazepam for seizure control. Correct hypoglycaemia and electrolyte disturbance. Naloxone does not reliably reverse tramadol-induced seizures.
  • Toxicity: Serotonin syndrome: agitation, confusion, tremor, clonus, hyperreflexia, hyperthermia, diaphoresis, tachycardia and hypertension, especially with serotonergic co-medication. · Stop tramadol and other serotonergic drugs. Provide supportive care, cooling and benzodiazepines. Consider cyproheptadine in specialist care. Severe cases need intensive care monitoring.
  • Toxicity: Cardiac and autonomic effects: tachycardia, hypertension, palpitations, QT interval prolongation, and rarely arrhythmias or cardiac arrest in severe overdose. · Obtain a 12-lead ECG and continuous cardiac monitoring. Correct hypoxia, electrolyte and acid-base abnormalities. Treat arrhythmias according to local protocols. Avoid other QT-prolonging drugs.
Antidotes & reversal
  • Naloxone · Reverses respiratory depression incompletely; seizures are managed with benzodiazepines.
Clinical notes
Tramadol is used for moderate pain when a weak opioid is appropriate, including some postoperative, musculoskeletal and neuropathic pain, but it is not a first-choice strong opioid and practice varies by country and formulary. It lowers the seizure threshold, can precipitate serotonin syndrome with serotonergic drugs, and can cause respiratory depression, sedation, dependence and withdrawal. Avoid or use with caution with MAOIs, SSRIs, SNRIs, tricyclics, triptans, other opioids, alcohol and CNS depressants. CYP2D6 inhibitors such as fluoxetine, paroxetine and bupropion may reduce analgesia, while enzyme inducers can reduce effect. Naloxone may partially reverse opioid effects but does not reliably reverse seizures or serotonin toxicity. It is a controlled drug in many countries, and scheduling differs by region. Counsel on driving, alcohol, constipation, nausea, and not stopping long-term treatment abruptly. Doses in teaching examples are for illustration only; check current prescribing information and local protocols.

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BNF; local formulary; manufacturer's summary of product characteristics; national controlled drug regulations